PB1880: A MULTICENTER PHASE 1 STUDY EVALUATING THE SAFETY AND TOLERABILITY OF HMPL-760 IN PATIENTS WITH PREVIOUSLY TREATED CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA OR OTHER NON-HODGKIN LYMPHOMA
Authors: B. Kahl, J. Cohen, R. Pillai, V. Jayaprakash, C. Wang, M. Hahka-Kemppinen, M. Kania, P. Zinzani
Journal: HemaSphere (2022)

Background: Covalent Bruton’s tyrosine kinase (BTK) inhibitors for the treatment of B-cell malignancies bind irreversibly to BTK. The most frequent mechanism of acquired resistance to covalent BTK inhibitors in chronic lymphocytic leukemia (CLL) is the development of mutations in the binding site, with a cysteine to serine substitution at position 481 (C481S). HMPL-760 is a potent, selective, and reversible BTK inhibitor which can inhibit B-cell malignant tumor growth of either BTKWT or mutant BTKC481S. In addition to its antitumor activity as a single agent, HMPL-760 showed synergistic and/or additive effects on B-cell lymphoma models when combined with other targeted therapies or chemoimmuno-therapy. Aims: This is a first in human phase 1, (NCT05176691) multicenter, dose escalation/expansion study to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-760 in patients with previously treated CLL/small lymphocytic lymphoma (SLL) or non-Hodgkin lymphoma (NHL). The primary objective of dose escalation is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of HMPL-760 and to evaluate the safety and tolerability in dose expansion. Secondary objectives for dose escalation/expansion are to assess the preliminary antitumor activity, PK, and PD of HMPL-760. Methods: In dose escalation, cohorts of up to 12 patients each will receive ascending oral doses of HMPL-760. The modified toxicity probability interval scheme-2 (mTPI-2)1,2 design will be used to perform dose escalation and MTD/RP2D determination, using dose increments from 25 mg to 400 mg once daily. The first 3 patients in each cohort will be administered a single oral dose of HMPL-760 on day 1 of the PK period and serial blood samples will be collected from days 1 to 4 for analysis of HMPL-760 plasma concentration. Dose limiting toxicities (DLTs) will be assessed during the first 28 days of continuous treatment, not including the PK period. Safety assessments will include DLTs, treatment emergent adverse event, serious adverse events, electrocardiograms and clinical laboratory tests. Efficacy assessments will include objective response rate, duration of response, clinical benefit rate, and progression-free survival. In dose expansion, ~25 patients each will be enrolled in the following cohorts: (1) patients with CLL/SLL who have failed prior BTK inhibitor therapy; (2) patients with mantle cell lymphoma who have failed prior BTK inhibitor therapy; (3) patients with marginal zone lymphoma who have failed prior BTK inhibitor therapy; (4) patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia who have failed prior BTK inhibitor therapy; (5) patients with CLL/SLL or other NHL who are intolerant to or failed BTK therapy and not meeting the definition for cohorts 1 to 4 if approved by the Sponsor; (6) patients with NHL not otherwise specified, inclusive of diffuse large B-cell lymphoma (DLBCL), DLBCL arising from follicular lymphoma (FL), Richter’s transformation, high grade B-cell lymphoma, or FL who have failed at least 2 prior systemic therapies, for which no curative therapy exists, and for whom treatment with a BTK inhibitor may be deemed appropriate. No formal hypothesis testing is planned for this study. 1. Guo et al. Contemp Clin Trials. 2017;58:23-33 2. Yang et al. Contemp Clin Trials. 2015;45:426-34 Results: N/A Summary/Conclusion: N/A